Infectious diseases, particularly those caused by viruses, presently result in a significant burden on human populations in terms of economic cost, morbidity and mortality. Many of viral diseases, including chickenpox, influenza, herpes, human immunodeficiency virus (HIV/AIDS), human papillomavirus (HPV), infectious mononucleosis, mumps, measles, rubella, shingles, viral gastroenteritis, viral hepatitis, viral meningitis, or viral pneumonia, can be fatal, particularly in vulnerable populations such as children or the elderly. Of particular concern is that the risk of various viral infections to humans rapidly spreading and potentially becoming pandemics has significantly increased in the last fifty years, in large part due to phenomenal increase in air travel. For example, in 2009, there were over 2.5 billion air travelers worldwide, with nearly 1 billion of those as international travelers crossing national borders. These concerns were borne out in 2009 with the rapid spread of a new strain of H1N1 influenza virus creating a pandemic.
Viruses are minute microorganisms having no cell structure, and they are broadly classified as DNA viruses or RNA viruses. In some sense, viruses are not living organisms in their own right since they completely depend upon host cells for all aspects that characterize living cells. For example, viruses require host cells for protein synthesis and energy production mechanisms, and viruses completely lack their own metabolic pathways. In short, viruses cannot exist without the cellular machinery of a host cell. Thus, viral infection presents a particularly difficult therapeutic challenge, in part due to the significant difficulty of designing therapeutic agents that attack the various without significant collateral damage to the host cells and other cells in the body.
Examples of an RNA virus causing a human disease include Japanese encephalitis virus, hepatitis C virus (HCV), and the like of the family Flaviviridae, Rotavirus and the like of the family Reoviridae, mumps virus, measles virus, and the like of the family Paramyxoviridae, influenza virus and the like of the family Orthomyxoviridae, and human immunodeficiency virus (HIV) and the like of the family Retroviridae. There exist three modes of viral infection: acute infection with significant disintegration of host cells; persistent infection with clinical symptoms that remain at relatively minor levels but become chronic; and latent infection with viruses that remain in a state in which no observable viral protein synthesis takes place for a long time period, although cancer is induced in some cases.
As noted above, influenza is caused by an RNA virus of the Orthomyxoviridae family. There are three types of these viruses and they cause three different types of influenza: type A, B and C. Influenza virus type A viruses infect mammals (humans, pigs, ferrets, horses) and birds. This is very important to mankind, as this is the type of virus that has caused worldwide pandemics. Influenza virus type B (also known simply as influenza B) infects only humans. It occasionally causes local outbreaks of flu. Influenza type C viruses also infect only humans. They infect most people when they are young and rarely causes serious illness.
Influenza viruses are enveloped viruses containing negative single-stranded RNA's which are segmented and encapsidated. The influenza virus envelope is characterized by the presence of two surface glycoproteins: hemagglutinin and neuraminidase. The influenza A and B virions are pleomorphic and are usually 80-120 nm in diameter. The influenza C virion has many distinctive properties and is thus distinguished from the closely related A and B virions.
It is estimated that millions of people in the United States—about 10% to 20% of U.S. residents—get influenza each year. The majority of this population generally recovers in one to two weeks. In some cases, however, complications can arise from an influenza infection. Those persons at highest risk for contracting complications from the flu include: persons over 50 years of age, children aged 6 to 23 months, women more than 3 months pregnant, persons living in a long-term care facility or institution, persons with chronic heart, lung, or kidney conditions, diabetes, or weakened immune system. Pneumonia, bronchitis, encephalitis, otitis media, rhinitis, and sinusitis are only a few examples of complications that result from an influenza infection. Moreover, the flu can make chronic health problems worse. For example, people with asthma may experience asthma attacks while they have the flu, and people with chronic congestive heart failure may have worsening of this condition that is triggered by the flu.
An average of about 36,000 people per year in the United States die from influenza, and 114,000 per year have to be admitted to the hospital as a result of the infection. Thus, influenza viruses have a major impact on morbidity leading to increases in hospitalization and in visits to health care providers. For example, high rates of hospitalization are often observed for subjects over 65 years of age and also for children less than 5 years of age.
Furthermore, the spread of influenza virus through a population can result in epidemics, which have considerable economic impact. High rates of mortality were observed due to influenza infection during the influenza epidemics of 1957, 1968 and 1977 (Fields Virology, Second Edition, Volume 1, pp. 1075-1152 (1990)). Periodically, the influenza virus causes a worldwide epidemic. For example, the influenza pandemic of 1918 reportedly caused about 20 million deaths worldwide and about 500,000 deaths in the United States (Medical Microbiology, Fourth Edition, University of Texas Medical Branch at Galveston (1996)).
Despite advances in the understanding of the biology of viruses, there is still a scarcity of compounds that are both potent, efficacious, and selective therapeutic agents for the treatment of viral diseases. These needs and other needs are satisfied by the present invention.